tbuckley/cabot-search huggingface dataset:
Metabolic Reprogramming in Hematologic Malignancies: Advances and Clinical Perspectives
Authors: Zhuoya Yu, Xiangxiang Zhou, Xin Wang
Journal: Cancer Research (2022)

Abstract Metabolic reprogramming is a hallmark of cancer progression. Metabolic activity supports tumorigenesis and tumor progression, allowing cells to uptake essential nutrients from the environment and use the nutrients to maintain viability and support proliferation. The metabolic pathways of malignant cells are altered to accommodate increased demand for energy, reducing equivalents, and biosynthetic precursors. Activated oncogenes coordinate with altered metabolism to control cell-autonomous pathways, which can lead to tumorigenesis when abnormalities accumulate. Clinical and preclinical studies have shown that targeting metabolic features of hematologic malignancies is an appealing therapeutic approach. This review provides a comprehensive overview of the mechanisms of metabolic reprogramming in hematologic malignancies and potential therapeutic strategies to target cancer metabolism.
CHD1 Promotes Sensitivity to Aurora Kinase Inhibitors by Suppressing Interaction of AURKA with Its Coactivator TPX2
Authors: Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Wei Shi, Chenling Meng, Jie Zhang, Kaitlyn Tremble, Xin Liang, Jian H. Song, Xu Feng, Vivien Van, Pingna Deng, Jared K. Burks, Ana Aparicio, Khandan Keyomarsi, Junjie Chen, Yue Lu, Himisha Beltran, Di Zhao
Journal: Cancer Research (2022)

Abstract Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies. Significance: CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.
Can Computed Tomography Scans Reliably Distinguish Pleuropulmonary Blastoma From Congenital Lung Malformations?
Authors: Andrew Jackson Murphy
Journal: JAMA Network Open (2022)

Abigail J. Engwall-Gill, MD; Sherwin S. Chan, MD, PhD; Kevin P. Boyd, DO; Jacqueline M. Saito, MD, MSCI; Mary E. Fallat, MD; Shawn D. St Peter, MD; Stephanie Bolger-Theut, DO; Eric J. Crotty, MD; Jared R. Green, MD; Rebecca L. Hulett Bowling, MD; Sachin S. Kumbhar, MD; Mantosh S. Rattan, MD; Cody M. Young, DO; Joseph K. Canner, MHS; Katherine J. Deans, MD, MHSc; Samir K. Gadepalli, MD, MBA; Michael A. Helmrath, MD; Ronald B. Hirschl, MD; Rashmi Kabre, MD; Dave R. Lal, MD, MPH; Matthew P. Landman, MD, MPH; Charles M. Leys, MD; Grace Z. Mak, MD; Peter C. Minneci, MD, MHSc; Tiffany N. Wright, MD; Shaun M. Kunisaki, MD, MSc; Midwest Pediatric Surgery Consortium; Jason Fraser; Cynthia Downard; Cheryl Adams; Thomas Sato; Daniel von Allmen; Jonathan Kohler; Daniel Ostlie; Sarah Fox
Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Authors: Peter Savas, Louisa L. Lo, Stephen J. Luen, Elizabeth F. Blackley, Jason Callahan, Kate Moodie, Courtney T. van Geelen, Yi-An Ko, Chen-Fang Weng, Lironne Wein, Maria João Silva, Andjelija Zivanovic Bujak, Miriam M. Yeung, Sarah Ftouni, Rodney J. Hicks, Prudence A. Francis, Chee Khoon Lee, Sarah-Jane Dawson, Sherene Loi
Journal: Cancer Discovery (2022)

Abstract There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER+) HER2− and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2− and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083–0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, P = 0.003). Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007
The Need for a Better-Quality Reporting System for Ambulatory and Outpatient Surgery—Surgical Quality Without Walls
Authors: Ava Ferguson Bryan, Sameer Nair-Desai, Thomas C. Tsai
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase
Authors: Xiaoqing Zhou, Shaoyang Zhao, Tingting Liu, Lu Yao, Meimei Zhao, Xiaoming Ye, Xiaowen Zhang, Qiang Guo, Pengfei Tu, Kewu Zeng
Journal: Acta Pharmaceutica Sinica B (2022)

Diabetes have been shown to cause progressive neuronal injury with pain and numbness via advanced glycation end-products (AGEs)-induced neuronal cell apoptosis; however, the valuable drug targets for diabetic neuropathy have been poorly reported so far. In this study, we discovered a natural small-molecule schisandrol A (SolA) with significant protective effect against AGEs-induced neuronal cell apoptosis. ATP6V0D1, a major subunit of vacuolar-type ATPase (V-ATPase) in lysosome was identified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conformation via targeting a unique cysteine 335 residue to activate V-ATPase-dependent lysosomal acidification. Interestingly, SolA-induced lysosome pH downregulation resulted in a mitochondrial-lysosomal crosstalk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mitochondrial homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidification, and also provide the first small-molecule template allosterically activating V-ATPase for preventing diabetic neuropathy.
P958: REAL-LIFE CURRENT STANDARD OF CARE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: SUBGROUP ANALYSES FROM THE LOCOMMOTION STUDY
Authors: H. Einsele, P. Moreau, V. De Stefano, D. Dytfeld, E. Angelucci, R. Benjamin, H. Goldschmidt, N. W. van de Donk, B. Besemer, C. Scheid, R. Vij, E. I. ’. Groen-Damen, M. Semerjian, V. Strulev, J. M. Schecter, T. Roccia, T. Nesheiwat, R. Wapenaar, K. Weisel, M.-V. Mateos
Journal: HemaSphere (2022)

Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have had previous triple-class exposure to a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody have limited treatment options and represent an urgent and unmet clinical need. LocoMMotion (NCT04035226) is the first prospective multinational study to assess real-life standard of care (SOC) treatment in pts with triple-class exposed RRMM. Aims: To assess efficacy in subgroups of pts treated with SOC therapies in the LocoMMotion study. Methods: All pts provided informed consent. This noninterventional study was conducted across 76 sites (63 in Europe, 13 in the United States). Pts were included if they had received ≥3 prior lines of therapy (LOT) or were refractory to a PI and an IMiD (double-refractory); received a PI, an IMiD, and anti-CD38 monoclonal antibody and had documented progressive disease during/after their last LOT. Real-life SOC therapies were defined as those used in local clinical practice. Responses and disease progression were based on International Myeloma Working Group criteria and assessed by response review committee. Patient subgroups were categorized according to the following baseline characteristics: age, Eastern Cooperative Oncology Group performance status (ECOG PS), renal function, International Staging System stage, extramedullary plasmacytoma, lactate dehydrogenase, bone marrow plasma cells percentage, number of prior LOT, triple-class or penta-drug exposure, and refractoriness. Results: 248 pts were enrolled as of May 21, 2021 (median follow-up: 11.0 months). Pts received a median of 4.0 (range: 1-20) cycles of SOC treatment. Efficacy outcomes were generally worse in pts with refractoriness to 3 classes of antimyeloma therapy, presence of extramedullary plasmacytomas, high LDH, and ECOG PS ≥1 compared with pts who did not have these characteristics (Table). Across all subgroups, overall response rate ranged from 20.0% to 43.1%. Efficacy outcomes were not affected by age and number of prior LOT. Image:Summary/Conclusion: In this first prospective study of real-life SOC treatment in pts with triple-class exposed RRMM, subgroup analyses indicate that specific pt and disease characteristics were associated with poor outcomes. Outcomes were poor in triple-class refractory and non-triple-class refractory pts; however, the latter subgroup had longer median progression-free survival. These data may help inform bridging strategies for chimeric antigen receptor T-cell therapy.
PB1758: TWENTY-ONE YEARS’ EXPERIENCE OF THE EORTC 58951 PROTOCOL FOR THE TREATMENT OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN THE SOUTH OF TUNISIA
Authors: I. Frikha, N. Siala, I. Turki, M. Mdhaffar, I. Ben Amor, M. Charfi, N. Louati, Y. Fakhfakh, F. Kallel, L. Khalifa, O. Kassar, S. Hadijji, H. Mnif, M. Elloumi
Journal: HemaSphere (2022)

Background: Childhood acute lymphoblastic leukemia (ALL) is a hematologic malignancy with high rate of cure. Aims: We report the experience of the clinical hematology department of Sfax-Tunisia for the treatment of childhood ALL with the EORTC 58951 protocol. Methods: From January 2000 to December 2020, we retrospectively studied the outcome of childhood ALL aged less 16 years, treated with the EORTC 58951 pediatric protocol. For those patients we studied the leukemia characteristics (sex ratio, white blood cell counts WBC, blast’s phenotype, cytogenetic abnormalities) and response to treatment: response to prophase, remission rate, risk group stratification, treatment related mortality (TRM) (induction and post induction death) and survival (overall survival OS and event free survival. Results: From January 2000 to December 2020, 284 children were treated with the EORTC 58951 protocol. Medium age was 7 years (range: 1 to 15 years). Sex ratio M/F was 1.53. WBC counts more than 100 G/L were observed respectively in 41, 44 and 15% of cases. The blast’s phenotype was B in 70%. Cytogenetic abnormalities were noted in 37% of cases. A good response to prophase was noted in 80% and complete remission in 92% of cases. The EORTC risk group stratification was Low Risk (LR) in 5%, Average Risk1 (AR1) in 39%, Average Risk2 (AR2) in 25% and Very High Risk (VHR) in 31%. TRM was 10%: induction rate death was 6% and post-induction rate death was 4%. Twenty-eight patients from VHR group with sibling familial donor underwent allograft. The relapse rate was 29% of all patients in remission; 4% for LR group, 39% for AR1 group, 18% for AR2 group and 39% for VHR group. At a follow up of 126 months, OS and EFS at 10 years were respectively 61% and 56%. Summary/Conclusion: At diagnosis, childhood ALL in our study had poor characteristics particularly higher rate of T phenotype of blasts, higher rate of leukocytosis more than 100 G/L, higher rate of VHR therapeutic group and higher rate of cortico-resistant regarding occidental series. Despite the acceptable results concerning remission rate but survival rates remain lower than those observed in the literature, this is explained mainly by the high rate of relapse (29% vs ≃15%). It can be improved our results by detecting high risk patient with MRD study especially for AR1 risk group and doing allograft for VHR patients.
Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies
Authors: Christine M Minnar, Paul L Chariou, Lucas A Horn, Kristin C Hicks, Claudia Palena, Jeffrey Schlom, Sofia R Gameiro
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immune checkpoint blockade (ICB) has achieved unprecedented success in treating multiple cancer types. However, clinical benefit remains modest for most patients with solid malignancies due to primary or acquired resistance. Tumor-intrinsic loss of major histocompatibility complex class I (MHC-I) and aberrations in antigen processing machinery (APM) and interferon gamma (IFN-γ) pathways have been shown to play an important role in ICB resistance. While a plethora of combination treatments are being investigated to overcome ICB resistance, there are few identified preclinical models of solid tumors harboring these deficiencies to explore therapeutic interventions that can bypass ICB resistance. Here, we investigated the combination of the epigenetic modulator entinostat and the tumor-targeted immunocytokine NHS-IL12 in three different murine tumor models resistant to αPD-1/αPD-L1 (anti-programmed cell death protein 1/anti-programmed death ligand 1) and harboring MHC-I, APM, and IFN-γ response deficiencies and differing tumor mutational burden (TMB). Methods Entinostat and NHS-IL12 were administered to mice bearing TC-1/a9 (lung, HPV16 E6/E7 + ), CMT.64 lung, or RVP3 sarcoma tumors. Antitumor efficacy and survival were monitored. Comprehensive tumor microenvironment (TME) and spleen analysis of immune cells, cytokines, and chemokines was performed. Additionally, whole transcriptomic analysis was carried out on TC-1/a9 tumors. Cancer Genome Atlas (TCGA) datasets were analyzed for translational relevance. Results We demonstrate that the combination of entinostat and NHS-IL12 therapy elicits potent antitumor activity and survival benefit through prolonged activation and tumor infiltration of cytotoxic CD8 + T cells, across αPD-1/αPD-L1 refractory tumors irrespective of TMB, including in the IFN-γ signaling-impaired RVP3 tumor model. The combination therapy promoted M1-like macrophages and activated antigen-presenting cells while decreasing M2-like macrophages and regulatory T cells in a tumor-dependent manner. This was associated with increased levels of IFN-γ, IL-12, chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL13 in the TME. Further, the combination therapy synergized to promote MHC-I and APM upregulation, and enrichment of JAK/STAT (janus kinase/signal transducers and activators of transcription), IFN-γ-response and antigen processing-associated pathways. A biomarker signature of the mechanism involved in these studies is associated with patients’ overall survival across multiple tumor types. Conclusions Our findings provide a rationale for combining the tumor-targeting NHS-IL12 with the histone deacetylase inhibitor entinostat in the clinical setting for patients unresponsive to αPD-1/αPD-L1 and/or with innate deficiencies in tumor MHC-I, APM expression, and IFN-γ signaling.
Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer
Authors: Ignasius Joanito, Pratyaksha Wirapati, Nancy Zhao, Zahid Nawaz, Grace Yeo, Fiona Lee, Christine L. P. Eng, Dominique Camat Macalinao, Merve Kahraman, Harini Srinivasan, Vairavan Lakshmanan, Sara Verbandt, Petros Tsantoulis, Nicole Gunn, Prasanna Nori Venkatesh, Zhong Wee Poh, Rahul Nahar, Hsueh Ling Janice Oh, Jia Min Loo, Shumei Chia, Lih Feng Cheow, Elsie Cheruba, Michael Thomas Wong, Lindsay Kua, Clarinda Chua, Andy Nguyen, Justin Golovan, Anna Gan, Wan-Jun Lim, Yu Amanda Guo, Choon Kong Yap, Brenda Tay, Yourae Hong, Dawn Qingqing Chong, Aik-Yong Chok, Woong-Yang Park, Shuting Han, Mei Huan Chang, Isaac Seow-En, Cherylin Fu, Ronnie Mathew, Ee-Lin Toh, Lewis Z. Hong, Anders Jacobsen Skanderup, Ramanuj DasGupta, Chin-Ann Johnny Ong, Kiat Hon Lim, Emile K. W. Tan, Si-Lin Koo, Wei Qiang Leow, Sabine Tejpar, Shyam Prabhakar, Iain Beehuat Tan
Journal: Nature Genetics (2022)

Abstract The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined ‘IMF’ classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F).
A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression
Authors: Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao
Journal: Journal of Clinical Investigation (2022)

Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury-induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury-induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data
Authors: Daniel A. Arber, Attilio Orazi, Robert P. Hasserjian, Michael J. Borowitz, Katherine R. Calvo, Hans-Michael Kvasnicka, Sa A. Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E. Bueso-Ramos, Jorge E. Cortes, Paola Dal Cin, Courtney D. DiNardo, Hervé Dombret, Eric J. Duncavage, Benjamin L. Ebert, Elihu H. Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A. Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S. Hobbs, Ronald Hoffman, Elias J. Jabbour, Jean-Jacques Kiladjian, Richard A. Larson, Michelle M. Le Beau, Mignon L.-C. Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G. Mullighan, Charlotte Niemeyer, Olatoyosi M. Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P. Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R. Savona, Charles A. Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A. Stock, Richard M. Stone, Martin S. Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M. Vannucchi, Paresh Vyas, Andrew H. Wei, Olga K. Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi
Journal: Blood (2022)
Nonoperative Management of Childhood Calvarial Langerhans-Cell Histiocytosis
Authors: Paul Steinbok, Alexander Cheong, David B Dix, Sanjiv Bhatia, Michael H Handler, David D Limbrick, Toba Niazi, Angela V Price, John Ragheb, Mark Souweidane, Mandeep S Tamber, David I Sandberg
Journal: New England Journal of Medicine (2022)